In recent years, there has been significant interest in the possibility that hematopoietic cell transplantation (HCT) may effectively treat severe autoimmune diseases (ADs). Existing clinical trials are testing high dose preparative regimens followed by autologous HCT for ADs. In pre-clinical rodent studies, we and others have found that whereas allogeneic HCT is highly effective at halting AD pathogenesis, congenic or syngeneic (equivalent to autologous) HCT is inconsistent in its curative effects. A major barrier that has prevented the use of allogeneic HCT to treat human AD has been the morbidity and mortality associated with the HCT procedure. However, the recent development of non-myeloablative regimens to condition patients of older age or medical co-morbidities for allogeneic HCT have demonstrated successful reduction in regimen-related toxicities. A non-myeloablative regimen consisting of total lymphoid irradiation (TLI) and rabbit anti-thymyocyte globulin (ATG) developed at our institution was used in a pilot study of patients with advanced stage malignancies. The rationale behind the TLI/ATG regimen was to reduce graft-versus host disease (GVHD)which remains problematic with other non-myeloablative regimens. The TLI/ATG regimen was well-tolerated and all patients achieved engraftment of donor HLA-matched hematopoietic cells. Furthermore, only one of 17 patients developed acute GVHD and 3 of 17 patients developed extensive chronic GVHD. All cases of GVHD were steroid responsive. This project proposes to extend the TLI/ATG allograft regimen to the patients with life-threatening systemic lupus erythematosus (SLE). The overall aims of the project are to assess the safety and efficacy of the TLI/ATG regimen in a selected SLE population. To date one SLE patient has undergone allogeneic HCT using this regimen and demonstrates promising results. This project will further aim to understand the way that this TLI/ATG-based HCT alter recipient immune responses. Immune reconstitution will be evaluated in pre- and post-transplant lymphocyte and antigen-presenting cell populations by phenotype analysis, in vitro mixed cellular assays, and novel antibody profiling using a proteomics approach. This project interacts with all projects in the Program Project Grant.